Sarcoidosis and fatigue
Sarcoidosis is a systemic granulomatous disease that affects all ethnic groups and ages. In
the United Kingdom the incidence of the disease is 5.0 cases per 100,000 patient years, with
a mean age at diagnosis of 47 years, frequently affecting patients of working age(Gribbin et
al). The cause is unknown and there is no cure(Iannuzzi et al). Many patients suffer from
debilitating fatigue for which there is presently no treatment.
Fatigue has been described as a "core symptom" of sarcoidosis, and is present in up to 80% of
patients(Marcellis et al). A "post-sarcoidosis chronic-fatigue syndrome" has been
described(James), denoting the presence of fatigue where there is no evidence of active
disease. The presence of this symptom has been shown to adversely affect quality of
life(Michielsen et al). Although there increased risk of obstructive sleep apnoea and
sleep-disordered breathing occurring in sarcoidosis patients(Michielsen et al; Drent et al)
the majority of patients have no identifiable cause for fatigue other than their sarcoidosis.
Both the British Thoracic Society(Bradley et al) and American Thoracic Society(Costabel et
al) produce guidelines for physicians treating people with sarcoidosis. Neither guideline
gives any advice on treatment of fatigue. Fatigue is a common problem in sarcoidosis. In a
study of 76 patients with sarcoidosis, 50.7% reported pathological levels of fatigue, defined
as a Fatigue Assessment Scale (FAS) score of greater than 21 units, compared with 8.6% of
controls. People reporting fatigue scores above 21, had poorer EuroQoL Visual Analogue Scale
(EQVAS) scores compared with people reporting fatigue scores of 21 or below (mean scores
0.561 vs 0.792 , p<0.001) (Unpublished data, Norfolk and Norwich University Hospital). This
shows that fatigue impacts upon quality of life in sarcoidosis.
Methylphenidate - a treatment for fatigue
Methylphenidate (and its isomer dexmethylphenidate), which is used to treat attention deficit
hyperactivity disorder(Keating et al), is an amphetamine-derivative which works by amplifying
dopamine signals through inhibition of dopamine reuptake and enhancement of extracellular
dopamine in the basal ganglia(Volkow et al). It has been used to treat fatigue in other
settings with good effect. In a placebo-controlled, double-blind trial in post-chemotherapy
participants with fatigue, methylphenidate exhibited a clinically significant reduction in
fatigue(Lower et al). Prior to the results from this trial, a Cochrane review of treatments
for cancer-related fatigue from 5 RCTs had shown an improvement in fatigue through
methylphenidate treatment, leading them to conclude "the current evidence supports the use of
psychostimulants in cancer-related fatigue"(Minton et al). Another trial investigated
methylphenidate for the treatment of fatigue in 109 HIV-positive patients over a 6-week
period. Methylphenidate improved fatigue on a visual analogue scale, with a 26.2 point
increase (maximum of 100) from baseline, with 41% of participants receiving the drug
demonstrating a greater than 50% improvement in visual analogue scale score(Breitbart et al).
In contrast, no difference between methylphenidate and placebo was seen in a cohort of 68
fatigued patients who had received radiotherapy for brain tumours followed over a 12 week
period(Butler et al).
In the case of sarcoidosis, so far only one small study has investigated the use of
dexmethylphenidate for fatigue(Lower et al). Ten patients were included in this double blind
crossover trial. Participants reported clinically and statistically significant improvements
in fatigue measured by both the FAS and the Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-F) score after 8 weeks of treatment, although no statistically
significant improvement was seen in six minute walk distance (6MWD) compared with placebo.
The drug was well tolerated; all participants completed the study and no significant increase
in side effects was noted between the patients receiving placebo and dexmethylphenidate.
Rationale for current study
Prior to designing a definitive study, issues about the feasibility of undertaking a
sufficiently large trial require to be resolved. Completed trials have only used
methylphenidate for 8-12 weeks, so sustainability of effect, tolerability of medications over
a long period and retention of participants within the trial are unknown. Whilst the use of
medications such as methylphenidate may not be used on a continuous basis in the clinical
setting, their use on a 6-12 month basis may not be unreasonable, hence the need to review
the effect of the medication over a longer period. Furthermore, it is unclear how many people
would be willing to participate in a longer trial , and how many potential participants would
be suitable for enrolment using our present inclusion and exclusion criteria. For this
reason, a feasibility trial is necessary before committing to a larger trial.
In addition, this trial will evaluate exercise and activity through both a modified shuttle
walk test (MSWT) and accelerometer-measured change in activity levels. Although
methylphenidate has not been shown to significantly improve 6MWD(Lower et al), a larger study
using a more responsive test may be required to evaluate exercise capacity in this setting.
This could be because as a self-paced test it is a sub-maximal exercise test - this has been
shown to be the case in a study of interstitial lung disease (ILD) patients (including
sarcoidosis) where peak oxygen uptake, carbon dioxide uptake and ventilation were all lower
during 6MWD than on cardiopulmonary exercise testing(Holland et al). By not reaching their
maximum exercise level this may make the test less responsive to change. This is particularly
relevant given that the ILD cohort who did not reach maximal exercise or oxygen uptake during
their 6MWD were likely to be much more limited in cardiopulmonary function than the cohort
anticipated to be enrolled in a study of treatment of fatigue and therefore much more likely
to get closer to their peak oxygen uptake during a 6MWD. Given that activity levels measured
by accelerometers in people with sarcoidosis is related to fatigue (Korenromp et al), this
trial will evaluate the feasibility of using them as an outcome measure in a clinical trial,
including whether participants will wear the devices for long enough (i.e. 4 days out of 7,
at least 10 hours per day) to get valid data for estimating daily activity levels.
Study Design
This is a parallel-arm RCT including 30 participants, randomised on a 1.5:1 basis in favour
of the active treatment arm (18 participants will receive methylphenidate, 12 will receive
placebo). The rationale of this trial is to determine the feasibility of designing and
performing a sufficiently large RCT in the future looking for proof of clinical effect of
methylphenidate in the treatment of sarcoidosis-associated fatigue. As a result, this study
is not powered to detect a clinical difference in a clinical outcome, although these will be
measured and analysed (the estimate of effect size will be used for future power
calculations). Therefore the primary outcomes regard feasibility and safety, not treatment
effect (see Outcome Measures section).
Participants will receive either methylphenidate or placebo for 24 weeks, with a further
assessment performed 6 weeks after completion of the trial. They will be carefully monitored
over the initial 6 weeks to ensure that they are stable on the drug - during this time they
will be seen every 2 weeks (at 0,2,4 and 6 weeks). Following this period they will be seen
less frequently (at 12 and 24 weeks, with postal questionnaires performed at 18 weeks) to
detect sustainability of effect. Determining if treatment effect is sustained over the second
half of the trial period will help to establish how long any future trial will need to be.
Although each participant is required to attend frequent visits to the hospital, this trial
has been designed in conjunction with sarcoidosis patients and ensures that participant
safety is paramount.